Regression and spreading of self-recognition during the development of autoimmune demyelinating disease

The autoimmune T cell repertoire in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) is characterized by CD4(+)T cells of the Th1 phenotype that recognize peptide determinants of central nervous system (CNS) myelin proteins in an MHC class II-restricted manner. Our recent studies and those performed by others have shown that progression to chronicity in EAE and MS is accompanied by a broadening of the T cell repertoire with time. This acquired neo-autoreactivity is commonly referred to as epitope spreading and is presumably the result of endogenous priming to new self-determinants during the CNS inflammation that accompanies disease onset and relapse. In the present study we extend our earlier observations by showing that disease progression in both EAE and MS is accompanied by two concurrent events, viz. (1) the spontaneous regression of the primary established autoimmune repertoire associated with disease onset, and (2) the emergence of the epitope spreading cascade associated with disease progression. Our data show that disease initiation and disease progression in both EAE and MS are typically associated with distinctly different autoimmune T cell repertoires. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an 'epitope du jour' and 'moving target' perspective.